Improved Visualization of Cortical Lesions in Multiple Sclerosis Using 7T MP2RAGE.

BACKGROUND AND PURPOSE: Cortical lesions are common and often extensive in multiple sclerosis but are difficult to visualize by MRI, leaving important questions about their clinical implications and response to therapy unanswered. Our aim was to determine whether cortical lesions are better visualized using magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) than T2*-weighted imaging on 7T MR imaging. MATERIALS AND METHODS: Brain MR imaging using T1-weighted MP2RAGE at 500-µm isotropic resolution, T2*-weighted gradient-echo, and T2*-weighted segmented echo-planar imaging sequences were collected for 13 patients with MS and 5 age-matched neurologically healthy controls on a 7T research system. One MS case underwent postmortem MR imaging including gradient-echo and MP2RAGE sequences, after which cortical lesions seen on MR imaging were assessed with immunohistochemistry. RESULTS: MP2RAGE detected 203 cortical lesions (median, 16 lesions/case; interquartile range, 15), compared to 92 with T2*gradient-echo (median, 7; interquartile range, 8; P < .001) and 81 with T2*EPI (median, 7; interquartile range, 5; P < .001). This increase in lesion number detected on MP2RAGE versus T2* was observed for juxtacortical, leukocortical, and intracortical lesions. Forty-three percent of all cortical lesions were identified only on MP2RAGE. White matter lesion volume correlated with total juxtacortical (r = 0.86, P < .001) and leukocortical lesion volume (r = 0.70, P < .01) but not intracortical lesion volume, suggesting that pathophysiology may differ by lesion type. Of 4 suspected lesions seen on postmortem imaging, 3 were found to be true cortical lesions while 1 represented postmortem tissue damage. CONCLUSIONS: A combination of MP2RAGE and T2*-weighted imaging at 7T improved detection of cortical lesions and should enable longitudinal studies to elucidate their spatiotemporal dynamics and clinical implications.

Patterns of white matter damage are non-random and associated with cognitive function in secondary progressive multiple sclerosis.

In multiple sclerosis (MS), white matter damage is thought to contribute to cognitive dysfunction, which is especially prominent in secondary progressive MS (SPMS). While studies in healthy subjects have revealed patterns of correlated fractional anisotropy (FA) across white matter tracts, little is known about the underlying patterns of white matter damage in MS. In the present study, we aimed to map the SPMS-related covariance patterns of microstructural white matter changes, and investigated whether or not these patterns were associated with cognitive dysfunction. Diffusion MRI was acquired from 30 SPMS patients and 32 healthy controls (HC). A tensor model was fitted and FA maps were processed using tract-based spatial statistics (TBSS) in order to obtain a skeletonised map for each subject. The skeletonised FA maps of patients only were decomposed into 18 spatially independent components (ICs) using independent component analysis. Comprehensive cognitive assessment was conducted to evaluate five cognitive domains. Correlations between cognitive performance and (1) severity of FA abnormalities of the extracted ICs (i.e. z-scores relative to FA values of HC) and (2) IC load (i.e. FA covariance of a particular IC) were examined. SPMS patients showed lower FA values of all examined patterns of correlated FA (i.e. spatially independent components) than HC (p < 0.01). Tracts visually assigned to the supratentorial commissural class were most severely damaged (z = - 3.54; p < 0.001). Reduced FA was significantly correlated with reduced IC load (i.e. FA covariance) (r = 0.441; p < 0.05). Lower mean FA and component load of the supratentorial projection tracts and limbic association tracts classes were associated with worse cognitive function, including executive function, working memory and verbal memory. Despite the presence of white matter damage, it was possible to reveal patterns of FA covariance across SPMS patients. This could indicate that white matter tracts belonging to the same cluster, and thus with similar characteristics, tend to follow similar trends during neurodegeneration. Furthermore, these underlying FA patterns might help to explain cognitive dysfunction in SPMS.

Sulcal and gyral crown cortical grey matter involvement in multiple sclerosis: A magnetisation transfer ratio study.

BACKGROUND: Histopathology has demonstrated extensive cortical grey matter (GM) demyelination in multiple sclerosis (MS), and suggests that sulcal folds may be preferentially affected, particularly in progressive MS. This has not been confirmed in vivo, and it is not known if it is relevant to clinical status. OBJECTIVES: To determine sulcal and gyral crown magnetisation transfer ratio (MTR) in MS cortical GM, and the MTR associations with clinical status. METHODS: We measured sulcal and gyral crown cortical GM MTR values in 61 MS patients and 32 healthy controls. Disability was measured using Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores. RESULTS: MTR values were reduced in sulcal and gyral crown regions in all MS subtypes, more so in secondary progressive (SP) MS than relapsing remitting (RR) MS, and similarly in primary progressive (PP) MS and RRMS. Sulcal MTR was lower than gyral crown MTR in controls, PPMS and RRMS patients, but not in SPMS. MTR correlated with clinical status in RRMS and SPMS, but not PPMS. CONCLUSIONS: Cortical pathology, as reflected by MTR, is present in all MS subtypes and most pronounced in SPMS. A preferential disease effect on sulcal cortical regions was not observed. Cortical MTR abnormalities appear to be more clinically relevant in relapse-onset rather than progressive-onset MS.

Design and synthesis of spiro derivatives of parthenin as novel anti-cancer agents.

Several novel spiro derivatives of parthenin (1) have been synthesized by the dipolar cycloaddition using various dipoles viz; benzonitrile oxides, nitrones and azides with exocyclic double bond of C ring (α-methylene-γ-butyrolactone). Majority of the compounds exhibited improved anti-cancer activity compared to the parthenin, when screened for their in vitro cytotoxicity against three human cancer cell lines viz., SW-620, DU-145 and PC-3. In vivo screening of select analog revealed improved anti-cancer activity with low mammalian toxicity as compared to parthenin. The results of the cytotoxicity pattern of these derivatives reveals the SAR of these sesquiterpinoid lactones and possible role of α,ß-unsaturated ketone of parthenin in inhibiting NF-kB. A mechanistic correlation of anti-cancer activity along with in vivo and western blotting experiments has been described.

Adjuvant sequential chemotherapy and radiotherapy in uterine papillary serous carcinoma.

PURPOSE: To evaluate the efficacy and toxicity of adjuvant combination of sequential chemotherapy followed by radiotherapy in uterine papillary serous carcinoma (UPSC). METHODS AND MATERIALS: From April 1994 to June 2003, 26 patients (median age 61.7 years, range 46.9-78.4) with UPSC were treated with a platinum-based chemoradiation protocol after definitive surgery. 9 patients were assigned as stage I (35%), 4 were stage II (15%), 11 were stage III (42%), and 2 were stage IV (8%) according to the FIGO staging for gynecological cancers. All patients underwent total hysterectomy, salpingo-oophorectomy, pelvic +/- perioartic lymph nodes dissection/sampling, omentectomy, and peritoneal washing. The adjuvant chemoradiation protocol consists of 4 cycles of platinum-based chemotherapy followed by pelvic irradiation and vaginal vault brachytherapy. In selected stage I patients with no or minimal myometrial invasion, only vault brachytherapy was given after adjuvant chemotherapy. RESULTS: After a median follow-up of 28 months (range 9-113 months), 14 (54%) patients were alive and free of disease. 12 out of these 14 patients were FIGO stage I/II. 9 patients (35%) had died (8 from distant metastases). The Kaplan-Meier 2-year and 5-year survival estimates were 69.5% and 57%, respectively. Only 4 (15%) patients had pelvic recurrence. None of the patients developed local vault recurrence. The treatment was well tolerated, only 1 patient developed congestive cardiac failure from the chemotherapy and 6 patients had grade 2 peripheral neuropathy on follow-up. CONCLUSION: In our series of UPSC patients treated with adjuvant chemotherapy followed by radiotherapy, local control can be achieved in a majority of patients. Distant failure remains the major cause of mortality. Further investigations into finding a more effective systemic therapy are required if improvement in outcome for this form of uterine cancer is to be achieved.

Intracranial germ cell tumour: experience of a Singaporean institution over 11-year period.

BACKGROUND: Intracranial germ cell tumours (IGCT) are rare. We present our experience in Therapeutic Radiology Department, National Cancer Centre, Singapore. METHODS: A retrospective study was conducted through case notes review on 25 patients with IGCT referred between January 1988 and January 1999. RESULTS: The median age at diagnosis was 13 years (range 6-22). The tumours were mainly pineal germinoma (72%). Median follow-up for living patients was 2.57 years (range 0.12-10.8). Median radiotherapy (RT) dose to whole brain, primary site and spine was 35.3,54 and 30 Gys respectively. Four to six cycles of BEP or JEB chemotherapy (CM) were given in 10 patients. As for the whole study group, the seven-year overall survival (OS) and recurrence-free survival (RFS) were 86% (95% CI 72-100) and 78% (95% CI 60-100) respectively. The 10-year OS and RFS were 65% (95% CI 36-100) and 78% (95% CI 60-100) respectively. The germinoma group had 75% 10-year OS and 86% 10-year RFS. Mixed germinoma and non-germinoma germ cell tumours (NGGCT) group had 50% one-year RFS and 44% two-year OS. Acute side-effects of RT and CM were minimal. There was no statistically significant difference in side-effects when treatment modalities were compared. CONCLUSION: In the treatment of intracranial germinoma, we recommend biopsy and CSRT. Primary chemotherapy (+/- low-dose cranial RT) should be used in the protocol or clinical trial settings. Chemo-radiotherapy is recommended for mixed germinoma and NGGCT. A multicentre trial is needed to address various controversial issues.

Liposomal VIP potentiates DNA synthesis in cultured oral keratinocytes.

The purpose of this study was to determine whether association of vasoactive intestinal peptide with sterically stabilized liposomes (VIP on SSL) amplifies DNA synthesis evoked by the peptide in cultured chemically transformed hamster oral keratinocytes (HCPC-1) and, if so, whether this response in mediated, in part, by SSL-induced inactivation of neutral endopeptidase 24.11 (NEP; EC 3.4.24.11) and angiotensin I-converting enzyme (ACE; EC 3.4.15.1), two ectoenzymes that modulate HCPC-1 cell growth, in these cells. We found that VIP (10(-9)-10(-6) M) alone elicited a modest, albeit significant, concentration-dependent increase in DNA synthesis in HCPC-1 cells that was maximal after 48-72-h incubation (p < 0.05). VIP on SSL potentiated DNA synthesis in these cells relative to VIP alone. The magnitude of VIP on SSL-induced responses was 1.2-1.6-fold higher than that of VIP alone with maximal effects observed at 10(-9) M and 10(-6) M after 72- and 48-h incubation, respectively. Empty SSL had no significant effects on DNA synthesis. Empty SSL and VIP on SSL had no significant effects on NEP 24.11 and ACE activity in HCPC-1 cells. Collectively, these data indicate that association of VIP with SSL potentiates DNA synthesis in cultured oral keratinocytes relative to VIP alone and that this response is not related to non-specific effects of SSL.

Surface-active properties of vasoactive intestinal peptide*.

The purpose of this study was to determine whether human vasoactive intestinal peptide (VIP) aggregates in aqueous solution and, if so, whether the peptide interacts with a biomimetic phospholipid monolayer and increases surface pressure. Using a custom-made Teflon trough containing HEPES buffer (pH 7.4) at room temperature and a surface tensiometer, we found that the critical micellar concentration (CMC) of VIP is 0.4 microM. Surface pressure of a dipalmitoylphosphatidylcholine (DPPC) monolayer spread over the HEPES buffer declined significantly over 120 min because of phospholipid decomposition. However, injection of VIP at concentrations above CMC into the subphase of the monolayer elicited a significant concentration-dependent increase in surface pressure that persisted for 120 min (P < 0.05). Unlike VIP, injection of [(8)Arg]-vasopressin at an equimolar concentration only prevented the time-dependent decline in DPPC monolayer surface pressure. Taken together, these data indicate that human VIP aggregates in aqueous solution and expresses surface-active properties at physiological concentrations in vitro. We suggest that these attributes could have a role in modulating the bioactive effects of the peptide in vivo.

Prognostic factors in 677 patients in Singapore with nondisseminated nasopharyngeal carcinoma.

BACKGROUND: The objective of the current study was to describe the survival of nasopharyngeal carcinoma (NPC) patients in Singapore, verify the prognostic value of the revised 1997 TNM staging system, and develop a multivariate prognostic model for NPC. In addition, the authors also examined the prognostic value of characteristics of lymph node spread and parapharyngeal involvement. METHODS: A prospectively maintained database containing clinical and computed tomography scan data was used to reclassify 677 NPC patients treated between 1992 and 1994 according to the new staging system. Records were linked with the death registry to ascertain the patient's vital status and date of death. Overall and stage specific survival were analyzed using the Kaplan-Meier method and the log rank test. Univariate and multivariate Cox proportional hazards regression analysis were used to obtain prognostic models. RESULTS: Two hundred seventy-four deaths (40.5%) occurred. The 5-year survival rate was 56.6% (95% confidence interval [95% CI], 52.3%, 60.7%). The stage specific 5-year survival rates were: Stage I, 88%; Stage IIA, 75%; Stage IIB, 74%; Stage III, 60%; Stage IVA, 35%; and Stage IVB, 28%. TNM stage was found to be a statistically significant prognostic factor (P < 0.0001). Cranial nerve (hazard ratio [HR]: 2.77), orbit (HR: 5.71), and intracranial involvement (HR: 2.46) conferred a particularly bad prognosis in univariate analysis. Independently significant prognostic factors were age; lymph node status; and paraoropharyngeal, cranial nerve, orbit, and nasal involvement. Among lymph node positive patients, independently significant prognostic lymph node characteristics were Ho level and laterality. Although parapharyngeal involvement appeared to be prognostically unimportant, paraoropharyngeal involvement distinguished a subgroup with a poorer prognosis (HR: 1.84; 95% CI, 1.45, 2.34; P < 0.0001). Lateral spread to the medial infratemporal fossa and beyond also was found to confer a poorer prognosis. CONCLUSIONS: The results of the current study show that the revised 1997 TNM staging system is prognostically useful. Subdivision into paraoropharyngeal involvement and using the medial infratemporal fossa to delineate prognostically significant lateral spread should be considered in future revisions.

Concurrent chemoradiotherapy followed by adjuvant chemotherapy in Asian patients with nasopharyngeal carcinoma: toxicities and preliminary results.

PURPOSE: Nasopharyngeal carcinoma (NPC) is endemic in Singapore. Nearly 60% of the patients diagnosed with NPC will present with locally advanced disease. The North American Intergroup study 0099 reported improved survival outcome in patients with locally advanced NPC who received combined chemoradiotherapy when compared to radiotherapy alone. Hence we explored the feasibility and efficacy of a similar protocol in our patients. METHODS AND MATERIALS: Between June 1996 and December 1997, 57 patients were treated with the following schedule as described. Radical radiotherapy (RT) of 66-70 Gy to the primary and neck with cisplatin (CDDP) 25 mg/m2 on days 1-4 given by infusion over 6-8 hours daily on weeks 1, 4, and 7 of the RT. This is followed by a further 3 cycles of adjuvant chemotherapy starting from week 11 from the first dose of radiation (CDDP 20 mg/m2/d and 5-fluorouracil [5-FU] 1 gm/m2/d on days 1-4 every 28 days). RESULTS: The majority of patients (68%) had Stage IV disease. About 54% of patients received all the intended treatment; 75% received all 3 cycles of CDDP during the RT phase and 63% received all three cycles of adjuvant chemotherapy. The received dose intensity of CDDP and 5-FU of greater than 0.8 was achieved in 58% and 60% of the patients respectively. Two treatment-related deaths due to reactivation of hepatitis B and neutropenic sepsis respectively, were encountered. At median follow-up of 16 months, 14 patients had relapsed, 12 systemically and 2 loco-regionally. CONCLUSION: Due to the acceptable tolerability of such a protocol in our cohort of patients, we have embarked on a Phase III study to confirm the results of the 0099 Intergroup study in the Asian context.

Small cell neuroendocrine carcinoma of the cervix with involvement of multiple pelvic nodes--A successfully treated case by multimodal approach.

Small cell neuroendocrine carcinoma of the cervix is very rare and is usually associated with dismal prognosis if treated by conventional surgery and radiotherapy even in early stage disease. This tumor is characterized by early lymphatic and hematogenous spread. Only one successfully treated case of small cell neuroendocrine carcinoma of the cervix with dissemination to the pelvic nodes had been reported before in the literature. We are reporting a case of small cell neuroendocrine carcinoma of the cervix with multiple pelvic nodal metastases including the common iliac nodes, which had been successfully treated with a multimodal approach including radical hysterectomy, pelvic/para-aortic lymphadenectomy, and postoperative chemotherapy using cisplatin-etoposide combinations and pelvic irradiation.

Primary non-Hodgkin's lymphoma of the uterine cervix: case report of long-term survival of two patients treated with surgery and radiotherapy.

Two patients with Stage 1EA primary non-Hodgkin's lymphoma of the uterine cervix were treated by surgery and radiotherapy in 1986 and 1987. On follow-up, over a period of 10 years, both are well and remain free of recurrence.

A review of patients with high-risk carcinoma of the cervix treated with combined surgery and postoperative radiotherapy.

From May 1992 to October 1995, 57 patients with early stage cervical carcinoma were treated with hysterectomy and postoperative pelvic radiotherapy because of the presence of adverse histopathologic features. On prospective follow-up and analysis, the clinical outcome for 50 of these patients showed a pelvic disease control rate of 90.9%, a disease-free survival of 80.6% and an overall survival of 86.3%. Of the 8 relapses, half occurred in the pelvis i.e., 2 in the vaginal vault and 2 in the pelvic side walls. No severe complications were observed, but there was a 20% long-term Radiation Therapy and Oncology Group (RTOG) grade 1 to 2 urinary bladder dysfunctional problem and 28% incidence of suprapubic and/or leg oedema.

Radiotherapy as local adjuvant treatment for endometrial carcinoma--a review of 45 patients.

Forty-five patients with endometrial carcinoma were treated with local postoperative adjuvant radiotherapy during the period 1992 to 1995. Radiotherapy technique comprised both external beam irradiation as well as high-dose-rate vaginal vault brachytherapy. The 5-year overall survival and relapse-free survival rates were 74% and 73%, respectively and poorly differentiated histology grade was associated with poorer prognosis. Only 1 patient developed an isolated vaginal vault recurrence and another 9 patients relapsed mainly at the distal anatomical sites. The main radiotherapy-related complications were vaginal adhesion and stenosis. Radiotherapy is therefore effective as local adjuvant treatment in reducing risk of local-regional relapse in endometrial carcinoma.

Neurodevelopmental outcome at age two years amongst very low birth weight infants: results from a district general hospital.

STUDY OBJECTIVES: To describe the survival and neurodevelopmental outcome at age 2 years of very low birth weight infants from routinely collected information in a district general hospital setting. DESIGN: Case note review and child health surveillance information was collected on all liveborn < 1,501 g infants born in our district general hospital over 4 years, 1989-1992. Main outcome measures were (a) death before discharge, (b) normal neurodevelopment at age 2 years, (c) minor impairment at age 2 years, (d) major impairment at age 2 years. Comparability with other published work was examined. SETTING: Rotherham District General Hospital, a maternity unit with neonatal intensive care facilities. Selected infants were transferred for continuing neonatal intensive care to a tertiary unit. Most infants were followed up to age 2 years in a dedicated clinic. SUBJECTS: Liveborn very low birth weight infants. MAIN RESULTS: Over the 4 year period there were 125 liveborn infants < 1,501 g; 93 (74%) survived to discharge home. Defined neurodevelopmental outcome measures were easily retrievable in 92 children at age 2 years from hospital case notes or child health surveillance records. Sixty-four children (70%) were neurodevelopmentally normal, 10 children (11%) had a major impairment (mostly cerebral palsy) and 18 (19%) had an isolated minor impairment. CONCLUSIONS: The incidence of major impairment amongst very low birth weight infants in our district general unit is broadly comparable with other published series. Outcome measures of neurodevelopmental status are available from routinely collected clinical information. The use of such measures to make detailed comparisons between units is problematical because of a wide range of confounding variables.

Patient profile and survival in 270 computer tomography-staged patients with nasopharyngeal cancer treated at the Singapore General Hospital.

This is a report analysing the patient profile and survival results in 270 patients with nasopharyngeal carcinoma treated with radiation therapy between July 1987 and December 1988. The patients had a median age of 52.6 months, and a male-female ratio of 2.5:1. Ninety-four percent of patients were Chinese. The commonest presentation was that of a neck mass (found in approximately 65% of patients). Approximately two-thirds presented with disease more advanced than Ho's stage II. At a median follow-up of 52.6 months, the 5-year actuarial survival rate was 53% and the freedom from relapse rate was 57%. One hundred and seven patients died within the observation period. Of these, 46 patients had disease in the post nasal space, 41 in the neck and 60 in sites outside the head and neck.

Early recognition of children with special educational needs: report from a district.

Health professionals involved in the pre-school child health surveillance programme need to identify those children who are likely to require a formal statement of special educational needs. Such children should be identified as early as possible, preferably by their fourth birthday. Each district needs to examine their programme and thereby identify factors associated with late recognition of such children. We report on our own practice and findings over a three-year period, including the factors associated with late recognition of special needs and efforts to improve the rate of early recognition.